Misoprostol Dispersible Tablet

ABSTRACT

The present invention relates to a solid pharmaceutical formulation comprising misoprostol or a pharmaceutically acceptable salt thereof. In particular, the invention relates to a dispersible tablet comprising misoprostol or a pharmaceutically acceptable salt thereof, providing alternative routes of administration. The tablet is particularly suited for cervical ripening, induction of labor, prevention and/or treatment of postpartum or post-abortion hemorrhage.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 16/870,556, filed on 8 May 2020, which is a continuation of U.S. application Ser. No. 15/324,395, now U.S. Pat. No. 10,688,072, filed 6 Jan. 2017 as the U.S. national phase of PCT/DK2015/050216, filed 10 Jul. 2015, which is a continuation of U.S. application Ser. No. 14/329,023, filed 11 Jul. 2014 and now abandoned, which PCT application claims priority to European Patent Application No. 14176821.8 filed 11 Jul. 2014. Each of the aforementioned applications is hereby incorporated by reference in its entirety.

The present invention relates to a solid pharmaceutical formulation comprising misoprostol or a pharmaceutically acceptable salt thereof. In particular, the invention relates to a dispersible tablet comprising misoprostol or a pharmaceutically acceptable salt thereof.

BACKGROUND

Prostaglandins (PGs) have been associated with the onset of labor in women. Naturally occurring PGs are potent stimulants of human uterine contractility at any stage of pregnancy and also cause cervical ripening.

Induction of labor is defined as the process of artificially stimulating the uterus to start labor. It may be performed by administering oxytocin or prostaglandins to the pregnant woman. Labor induction is one of the most frequent procedures in pregnant women.

Cytotec and Misofar are commercially available misoprostol products, which comprise an extended release agent, hydrogenated castor oil.

The International patent application WO 2006/125450 A1 mentions the possibility of oral, sublingual, rectal or vaginal administration of misoprostol used in obstetric practice for controlling post-partum and post-abortive bleeding, and inducing labor or abortion. This application fails to disclose a pharmaceutical dosage form suitable for the mentioned administration forms.

The International patent application WO 2006/133048 A2 relates to a controlled release pharmaceutical gel for vaginal administration, the pharmaceutical gel comprising misoprostol, a cellulose derivative and a polyol, wherein the gel is a substantially nonaqueous gel which forms a hydrogel when placed in a vaginal tract.

The International patent application WO 2014/016394 A1 relates to the use of misoprostol for the induction of labor in a pregnant female, and in particular to the use of a sustained delivery device or insert containing 200 μg misoprostol for intravaginal use.

The International patent application WO 2007/035953 discloses vaginal tablets comprising misoprostol. The disclosed tablets comprise 100 μg misoprostol. A purported immediate release vaginal tablet and a sustained release vaginal tablet are disclosed, wherein the purported immediate release vaginal tablet are described as adhering to a tilted glass plate when placed on drops of water. Embodiments of the tablets are purported to adhere to an epithelial membrane. The vaginal tablets comprise lactose monohydrate, hydroxypropyl methylcellulose, corn starch and magnesium stearate. The vaginal tablets are manufactured by method steps comprising wet granulation, followed by drying in a fluid bed. The disclosed indications comprise cervical ripening and uterine contractions but not human labor.

SUMMARY OF THE INVENTION

Known misoprostol formulations for labor induction comprises at least one extended release agents and/or is intended for sustained delivery. In particular, existing misoprostol products for vaginal use comprise an extended release agent, such as hydrogenated castor oil, and/or are supposed to adhere to the vaginal tract of a subject.

There is a need for a misoprostol product which may provide a consistent dose irrespective of the route of administration, such as vaginal, oral or sublingual.

No misoprostol products for oral or sublingual use have yet been approved by regulatory agencies for induction of labor.

There is a need for a misoprostol product which is developed for both sublingual and oral administration, as guidelines on a national level as well as at the level of the individual hospital may suggest use of misoprostol through either route of administration.

These and other needs are met by aspects and embodiments of the present invention.

According to an aspect the present invention concerns a pharmaceutical composition comprising misoprostol or a pharmaceutically acceptable salt thereof, allowing an administration form selected among sublingual, oral and vaginal administration.

According to another aspect the invention concerns a method for obtaining cervical ripening or the induction of labor comprising administration of a pharmaceutical composition according to the invention. Preferably, the pharmaceutical formulation is used for female human subjects.

According to a third aspect the invention concerns a method for the manufacture of a pharmaceutical composition of the invention, wherein said pharmaceutical composition is a tablet and said method comprises a step of compression.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flow chart showing the manufacturing process for a misoprostol tablet of the present invention.

FIG. 2A shows misoprostol tablets before being subjected to a disintegration experiment. Tablet A is on the left side, Cytotec (a prior art misoprostol preparation) is on the right side.

FIG. 2B shows the tablets of FIG. 2A at 3 seconds after being placed in beakers with a few drops of water.

FIG. 2C shows the tablets of FIG. 2A at 7 seconds after being placed in beakers with a few drops of water.

FIG. 2D shows the tablets of FIG. 2A at 15 seconds after being placed in beakers with a few drops of water.

FIG. 3A shows precipitate from Mixture I remaining on screens #20, #30, #40, #60, #80, and #100 as described in Example 5.

FIG. 3B shows precipitate from Mixture II remaining on screens #20, #30, #40, #60, #80, and #100 as described in Example 5.

DETAILED DESCRIPTION

According to an embodiment, the present invention concerns a pharmaceutical composition comprising misoprostol or a pharmaceutically acceptable salt thereof, allowing an administration form selected among buccal, sublingual, oral and vaginal administration.

According to an embodiment, the present invention concerns the pharmaceutical composition, wherein said pharmaceutical composition allows sublingual administration.

A phamacokinetic study in pregnant woman, who was to terminate their pregnancy before 12 weeks, investigated plasma levels after administration of 400 mcg misoprostol (Tang O S, Schweer H, Seyberth H W, Lee S W, Ho P C; Pharmacokinetics of different routes of administration of misoprostol. Hum Reprod 2002 February; 17(2):332-6). Sublingual administration provided a larger peak in plasma concentration of misoprostol than oral and vaginal, and oral administration provided a larger peak than vaginal administration.

While this would point to using the sublingual administration route, no one has successfully produced a sublingual misoprostol product before the present invention. Sublingual administration would appear to offer faster effective administration of misoprostol. This is likely to provide better efficacy and fewer side effects, as adjusting the dosage becomes easier.

According to an embodiment, the present invention concerns the pharmaceutical composition, wherein said pharmaceutical composition allows any administration form selected among sublingual and oral administration.

According to an embodiment, the present invention concerns the pharmaceutical composition, wherein said pharmaceutical composition allows any administration form selected among sublingual, oral and vaginal administration.

Misoprostol product of the prior art are designed to be placed in the vagina for a longer time period, inherently carrying the risk of falling out. Due to the requirement of the present composition of a very small amount of liquid, it appears to be suitable for a vaginal environment.

Providing a product which combines oral, sublingual and vaginal administration is complicated by the fact that oral administration have to take into account the varying pH conditions in the gastrointestinal tract, depending on location and timing of administration.

According to an embodiment, the present invention concerns the pharmaceutical composition, comprising a disintegrant comprising cross-linked PVP, preferably crospovidone. According to a preferred embodiment, the disintegrant is a superdisintegrant.

The cross-linked form of PVP is used as a disintegrant in pharmaceutical tablets. Polyvinylpolypyrrolidone (polyvinyl polypyrrolidone, PVPP, crospovidone, crospolividone or E1202) is a highly cross-linked modification of polyvinylpyrrolidone (PVP), making it insoluble in water, though it still absorbs water and swells very rapidly generating a swelling force. This property makes it useful as a disintegrant in tablets.

Crospovidone may provide rapid disintegration in the mouth, and is particularly preferred for a pharmaceutical composition of the invention for buccal or sublingual administration.

Disintegrating agents are substances routinely included in the tablet formulations to aid in the break up of the compacted mass when it is put into a fluid environment. They promote moisture penetration and dispersion of the tablet matrix. In recent years, several newer disintegrants have been developed known as “Superdisintegrants”. These newer substances are more effective at lower concentrations with greater disintegrating efficiency and mechanical strength. On contact with water the superdisintegrants swell, hydrate, change volume or form and produce a disruptive change in the tablet. Effective superdisintegrants provide improved compressibility, compatibility and have little negative impact on the mechanical strength of formulations. Commonly available superdisintegrants along with their commercial trade names are briefly described herewith.

Modified starches: Sodium starch glycolate which is the sodium salt of a carboxymethyl ether of starch. It is usually effective at a concentration of 2-8%. It can take up more than 20 times its weight in water and the resulting high swelling capacity combined with rapid uptake of water accounts for its high disintegration rate and efficiency. It is available in various grades i.e. Type A, B and C, which differ in pH, viscosity and sodium content.

Modified celluloses, Carboxymethylcellulose and its derivative (Croscarmellose Sodium): Cross-linked sodium carboxymethylcellulose is a white, free flowing powder with high absorption capacity. It has a high swelling capacity and thus provides rapid disintegration and drug dissolution at lower levels. It also has an outstanding water wicking capability and its cross-linked chemical structure creates an insoluble hydrophilic, highly absorbent material resulting in excellent swelling properties. Its usual recommended concentration is 0.5-2.0%, which can be used up to 5.0% L-HPC (Low substituted Hydroxy propyl cellulose). It is insoluble in water, swells rapidly and is usually used in the range of 1-5%. The grades LH-11 and LH-21 exhibit the greatest degree of swelling.

Cross-linked polyvinylpyrrolidone is a completely water insoluble polymer. It rapidly disperses and swells in water but does not gel even after prolonged exposure. The rate of swelling is highest among all the superdisintegrants and is usually effective at 1-3%. It acts by wicking, swelling and possibly some deformation recovery. The polymer has a small particle size distribution that imparts a smooth mouth feel to dissolve quickly.

Soy polysaccharide is a natural super disintegrant that does not contain any starch or sugar so can be used in nutritional products. Cross-linked alginic acid is insoluble in water and disintegrates by swelling or wicking action. It is a hydrophilic colloidal substance, which has high sorption capacity. It is also available as salts of sodium and potassium. Gellan gum is an anionic polysaccharide of linear tetrasaccharides, derived from Pseudomonas elodea having good superdisintegrant property similar to the modified starch and celluloses. Xanthan Gum derived from Xanthomonas campestris is official in the USP with high hydrophilicity and low gelling tendency. It has low water solubility and extensive swelling properties for faster disintegration. Calcium Silicate It is a highly porous, lightweight superdisintegrant, which acts by wicking action. Ion exchange resins The INDION 414 has been used as a superdisintegrant.

Superdisintegrants, such as natural or synthetic superdisintegrants, may be used for the present pharmaceutical compositions. Natural superdisintegrants used in formulations, comprise, but are not limited to the group consisting of: Cassia fistula gum, LepidumSativum, Locust Bean gum, Plantago ovate Mucilage, Seed powder, Plantago ovata Husk powder, and Treated Agar. Synthetic Superdisintegrants used in formulations, comprise, but are not limited to the group consisting of: crospovidone, Sodium Starch glycolate, Croscarmellose sodium (Ac-Di-Sol), kollidon CL, B-cyclodextrin, and Citric Acid and Sodium bicarbonate.

According to an embodiment, the present invention concerns the pharmaceutical composition, comprising at least two disintegrants.

According to an embodiment, the present invention concerns the pharmaceutical composition, wherein at least one of said at least two disintegrants is a cross-linked carboxymethylcellulose, preferably croscarmellose sodium.

A suitable disintegrant is a modified cellulose, preferably a modified carboxymethylcellulose, more preferred a crosslinked polymer of carboxymethylcellulose, preferably croscarmellose. Croscarmellose sodium is an internally cross-linked sodium carboxymethylcellulose for use as a superdisintegrant in pharmaceutical formulations. The cross-linking reduces water solubility while still allowing the material to swell (like a sponge) and absorb many times its weight in water. As a result, it provides superior drug dissolution and disintegration characteristics, thus improving formulas subsequent bioavailability by bringing the active ingredients into better contact with bodily fluids.

According to an embodiment, the present invention concerns the pharmaceutical composition, wherein said at least two disintegrants uses different mechanisms of disintegration. The expression “different mechanisms” also covers the case of partly overlap between the different mechanisms.

Disintegrants may be classified by mechanism of disintegration as noted below.

Disintegrants classified by mechanism of disintegration Mechanism of Examples of disintegration Method disintegrants I. Swelling The particles of the Croscarmellose sodium disintegrant swells when Starch hydrated. The swelling Polyplasdone XL 10 pressure destroys the interaction between the other particles. II. Porosity and Facilitate the movement of Croscarmellose sodium Capillary Action fluid into the tablet. Polyplasdone XL 10 (Wicking) III. Disintegrating Electric repulsive forces particle/Particle between particles arise repulsive forces when hydrated. IV. Deformation The compression of tablets Starch deform the particles, when Polyplasdone XL 10 in contact with water the particles return to their original size. V. Chemical Inside the tablet acid and reaction (Acid-Base base react and CO₂ is reaction) released creating a pressure that breaks the tablet apart. Highly sensitive to humidity and temperature. VI. Enzymatic Enzymes present in the Reaction body breaks down the binder of the tablet.

According to an embodiment, the present invention concerns the pharmaceutical composition, wherein said at least two disintegrants uses mechanisms of disintegration comprising swelling, porosity and capillary action, and deformation. In other words preferably all of the mechanisms, I. (swelling), II. (wicking) and IV. (deformation) are covered by said at least two disintegrants.

According to an embodiment, the present invention concerns the pharmaceutical composition, wherein said at least two disintegrants are superdisintegrants.

According to an embodiment, the present invention concerns the pharmaceutical composition comprising a disintegrant which is starch, preferably maize starch.

According to an embodiment, the present invention concerns the pharmaceutical composition, further comprising at least one superdisintegrant.

According to an embodiment, the present invention concerns the pharmaceutical composition, wherein said pharmaceutical composition comprises an excipient selected among the group consisting of Maize starch (also known as Corn starch), Potato starch, Pea starch, Rice starch, Tapioca starch (also known as Cassava or Manioc starch), Wheat starch, and Modified starch.

Formerly, Potato starch was commonly used as a disintegrant. Recently, the use of so-called superdisintegrants such as crospovidone, croscarmellose sodium, and sodium starch glycolate have become more popular.

Maize starch suffers from the drawback that tablets comprising maize starch tend to be hygroscopic and thus unstable. It has surprisingly been discovered that starch, in particular maize starch, is particularly preferred for solving the problems of the present invention. This is in particular true, if starch is combined with another disintegrant, preferably at least one superdisintegrant, more preferred at least two superdisintegrants.

According to an embodiment, the present invention concerns the pharmaceutical composition, wherein said pharmaceutical composition comprises maize starch.

According to an embodiment, the present invention concerns the pharmaceutical composition, wherein said pharmaceutical composition comprises an amount of disintegrant of 1-50%, preferably 2-30%, more preferred 3-25%, preferably 5-20%, more preferred 6-15%, preferably 8-12%, more preferred about 10%.

According to an embodiment, the present invention concerns the pharmaceutical composition, wherein said pharmaceutical composition comprises an amount of superdisintegrant of 1-50%, preferably 2-30%, more preferred 3-25%, preferably 5-20%, more preferred 6-15%, preferably 8-12%, more preferred about 10%.

According to an embodiment, the present invention concerns the pharmaceutical composition, wherein said pharmaceutical composition comprises an amount of croscarmellose sodium of 1-50%, preferably 2-30%, more preferred 3-25%, preferably 5-20%, more preferred 6-15%, preferably 8-12%, more preferred about 10%.

According to an embodiment, the present invention concerns the pharmaceutical composition, wherein said pharmaceutical composition comprises an amount of crospovidone of 1-50%, preferably 2-30%, more preferred 3-25%, preferably 5-20%, more preferred 6-15%, preferably 8-12%, more preferred about 10%.

According to an embodiment, the present invention concerns the pharmaceutical composition, wherein said pharmaceutical composition comprises an amount of starch of 1-50%, preferably 2-30%, more preferred 3-25%, preferably 5-20%, more preferred 6-15%, preferably 8-12%, more preferred about 10%.

According to an embodiment, the present invention concerns the pharmaceutical composition, wherein said pharmaceutical composition comprises an amount of maize starch of 1-50%, preferably 2-30%, more preferred 3-25%, preferably 5-20%, more preferred 6-15%, preferably 8-12%, more preferred about 10%.

According to an embodiment, the present invention concerns the pharmaceutical composition, wherein said pharmaceutical composition comprises an amount of microcrystalline cellulose of 1-99%, preferably 5-98%, more preferred 10-97%, preferably 20-95%, more preferred 30-90%, preferably 40-85%, more preferred 50-80%, preferably 60-75%, more preferred about 70%.

According to an embodiment, the present invention concerns the pharmaceutical composition, wherein said pharmaceutical composition comprises an amount of flow agent of 0.1-10%, preferably 0.2-5%, more preferred 0.3-4%, preferably 0.5-3%, more preferred 0.8-2%, preferably about 1%.

According to an embodiment, the present invention concerns the pharmaceutical composition, wherein said flow agent is colloidal silicon dioxide.

According to an embodiment, the present invention concerns the pharmaceutical composition, having a content of misoprostol or a pharmaceutically acceptable salt thereof, selected among 0.5-1000, 1-500, 2.5-250, 5-100, 10-50, 20-30, and 25 μg. In the case of a pharmaceutically acceptable salt the amount is preferably equivalent to an amount of misoprostol selected among 0.5-1000, 1-500, 2.5-250, 5-100, 10-50, 20-30, and about 25 μg.

According to an embodiment, the present invention concerns the pharmaceutical composition having a disintegration time of no more than 15 minutes, preferably less than 15 minutes, more preferred less than 10 minutes, preferably less than 5 minutes, more preferred less than 3 minutes, preferably less than 2 minutes, more preferred less than 1 minute, preferably less than 45 seconds, more preferred less than 30 seconds, preferably less than 25 seconds, more preferred less than 20 seconds, preferably less than 15 seconds, more preferred less than 10 seconds, preferably less than 9 seconds, more preferred less than 8 seconds, preferably less than 7 seconds, more preferred less than 6 seconds.

The disintegration time is preferably measured using Disintegration apparatus A according to European Pharmacopoeia 8.0, placing one tablet in each of the 6 tubes of the basket without disc. The apparatus is operated using water medium as the immersion fluid, maintained at 37±2° C.

Short disintegration time does not only allow sublingual administration, but surprisingly appears to allow vaginal administration without the need of an extended release agent and/or adherence to the vaginal tract. A few drops of water, such as about ten drops or less, are sufficient to disintegrate compositions of the present invention. Thus, both sublingual and vaginal administration may be feasible.

Fast dissolving drug delivery provides a number of advantages, comprising improved patient compliance, ease of swallowing, no water needed, and accuracy of dosage (Walid Habib, Raj Khankari, and John Hontz, “Fast-Dissolve Drug Delivery Systems”, Critical Reviews in Therapeutic Drug Carrier Systems, 17(1):61-72(2000)).

According to an embodiment, the present invention concerns the pharmaceutical composition, wherein said disintegration time is measured initially after manufacture, preferably 3 months after manufacture, more preferred 6 months after manufacture, preferably 9 months after manufacture, more preferred 12 months after manufacture, preferably 18 months after manufacture, more preferred 24 months after manufacture.

According to an embodiment, the present invention concerns the pharmaceutical composition, which allows dispersion of one or more of said pharmaceutical compositions in 100 ml water at 25° C. within 15 minutes, preferably within 10 minutes, more preferred within 5 minutes, preferably within 3 minutes, more preferred within 2 minutes, preferably within 1 minute, upon stirring, thereby providing a dispersion; said dispersion passing through a sieve screen with a nominal mesh aperture of 710 μm.

According to an embodiment, the present invention concerns the pharmaceutical composition, which allows dispersion of one or more of said pharmaceutical compositions in 100 ml water at 25° C. within 15 minutes, preferably within 10 minutes, more preferred within 5 minutes, preferably within 3 minutes, more preferred within 2 minutes, preferably within 1 minute, substantially without stirring, thereby providing a dispersion; said dispersion passing through a sieve screen with a nominal mesh aperture of 710 μm. The expression “substantially without stirring” means that the pharmaceutical composition provides a dispersion spontaneously upon contact with water without the need of stirring, shaking or other form of agitation, or stirring up to a speed of 1 RPM.

According to an embodiment, the present invention concerns the pharmaceutical composition, which is a dispersible tablet.

According to an embodiment, the present invention concerns the pharmaceutical composition, wherein said pharmaceutical composition is a tablet.

According to an embodiment, the present invention concerns the pharmaceutical composition, further comprising a coating. While a preferred embodiment is a tablet without coating, another alternative is a tablet having a coating, e.g. to improve storage stability.

According to an embodiment, the present invention concerns the pharmaceutical composition, further comprising at least one excipient, preferably selected among diluents, disintegrants, binders, glidants, lubricants, and coatings.

An excipient is generally a pharmacologically inactive substance. Examples include, but are not limited to, diluents, disintegrants, binders, glidants, lubricants, and coatings. Other examples of suitable excipients may be found in Handbook of Pharmaceutical Excipients, 7^(th) Ed. by Rowe, Raymond C. et al., Pharmaceutical Press, London.

Diluents are inactive ingredients that are added to tablets and capsules in addition to the active drug. Some very common diluents in tablets include starch, cellulose derivatives, and magnesium stearate (also a lubricant). Diluents fill out the size of a tablet or capsule, making it practical to produce and convenient for the consumer to use. By increasing the bulk volume, diluents make it possible for the final product to have the proper volume for patient handling. A good diluent must be inert, compatible with the other components of the formulation, non-hygroscopic, relatively cheap, compactable, and preferably tasteless or pleasant tasting. Plant cellulose (pure plant diluent) is a popular diluent in tablets or hard gelatin capsules. Dibasic calcium phosphate is another popular tablet diluent. A range of vegetable fats and oils can be used in soft gelatin capsules. Other examples of diluents include: lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate.

Disintegrants may expand and dissolve when wet causing the tablet to break apart. They ensure that when the tablet is in contact with water, it rapidly breaks down into smaller fragments, facilitating dissolution or dispersion. Examples of disintegrants include, but are not limited to: crosslinked polymers, such as crosslinked polyvinylpyrrolidone (crospovidone), and crosslinked sodium carboxymethyl cellulose (croscarmellose sodium); and the modified starch sodium starch glycolate. Specific examples further include Indion 414, L-HPC, and pregelatinised starch.

Binders hold the ingredients in a tablet together. Binders ensure that tablets and granules can be formed with required mechanical strength, and give volume to tablets. Examples of binders include: saccharides and their derivatives: disaccharides, sucrose, lactose; polysaccharides and their derivatives, such as starches, cellulose or modified cellulose, such as microcrystalline cellulose and cellulose ethers such as hydroxypropyl cellulose (HPC); sugar alcohols such as xylitol, sorbitol or maltitol; further Protein: gelatin; and Synthetic polymers: polyvinylpyrrolidone (PVP), polyethylene glycol (PEG). Examples include gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, starch, sucrose and polyethylene glycol. Other examples include cellulose, methyl cellulose, polyvinylpyrrolidone and polyethylene glycol.

Glidants are used to promote powder flow by reducing interparticle friction and cohesion. These are used in combination with lubricants as they have no ability to reduce die wall friction. Examples include fumed silica, talc, and magnesium carbonate.

Lubricants are agents added to tablet and capsule formulations to improve certain processing characteristics. Lubricants inter alia prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall. Common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid are examples of lubricants used in tablets or hard gelatin capsules.

Coatings protect ingredients from deterioration by moisture in the air and make large or unpleasant-tasting tablets easier to swallow. For most coated tablets, a cellulose ether hydroxypropyl methylcellulose (HPMC) film coating is used which is free of sugar and potential allergens. Occasionally, other coating materials are used, for example synthetic polymers, shellac, corn protein zein or other polysaccharides. A specific example is Opadry. Capsules are coated with gelatin.

According to an embodiment, the present invention concerns the pharmaceutical composition, for cervical ripening or the induction of labor.

According to an embodiment, the present invention concerns a method for obtaining cervical ripening or the induction of labor comprising administration of a pharmaceutical composition according to any of the preceding claims. Preferably the pharmaceutical formulation is used for female human subjects.

According to an embodiment, the present invention concerns the method, wherein 25 μg misoprostol, or an equivalent amount of pharmaceutically acceptable salt thereof, is administered orally or sublingually every 2-4 hours or vaginally every 6 hours.

According to an embodiment, the present invention concerns the method, wherein 25 misoprostol, or an equivalent amount of pharmaceutically acceptable salt thereof, is administered orally or sublingually every 2-4 hours.

According to an embodiment, the present invention concerns the method for the manufacture of a pharmaceutical composition, wherein said pharmaceutical composition is a tablet and said method comprises a step of compression.

According to an embodiment, the present invention concerns the method, wherein said tablet is manufactured by a step of dry mixing followed by a step of direct compression.

All cited references are incorporated by reference.

The accompanying Figures and Examples are provided to explain rather than limit the present invention. It will be clear to the person skilled in the art that aspects, embodiments and claims of the present invention may be combined.

Unless otherwise mentioned, all percentages are in weight/weight. Unless otherwise mentioned, all measurements are conducted under standard conditions (ambient temperature and pressure).

EXAMPLES Example 1: Composition of the Invention

The following ingredients were used to manufacture tablets:

Ingredient mg/Tablet Ascribed function Misoprostol 2.50 API (as 1% HPMC dispersion) Microcrystalline Cellulose 69.5 Binder/Diluent/ (PH112) disintegrant Starch Plain (maize starch) 10.0 Diluent/disintegrant Croscarmellose Sodium 10.0 Super disintegrant (Ac-di-sol) Polyplasdone XL 10 10.0 Super disintegrant (Crospovidone) Colloidal Silicon Dioxide 1.00 Improves flow properties 103.0 Misoprostol (as 1% HPMC dispersion) provides 2.50 mg/100 = 25 μg misoprostol per tablet.

FIG. 1 provides a flow chart of the manufacturing process.

Key steps of the applied process, which follows the procedure of FIG. 1, are described as follows:

Sifting:

Misoprostol and other excipients pass through 30# sieve.

Geometrical Mixing:

Step 1: Manually mix 75 g of Misoprostol (As 1 HPMC dispersion) with 75 g of Microcrystalline cellulose PH 112.

Step 2: Mix 150 g of step 1 blend with 150 g of Microcrystalline cellulose PH 112.

Step 3: Mix 300 g of step 2 blend with 300 g of Microcrystalline cellulose PH 112.

Step 4: Mix 600 g of step 3 blend with 600 g of Microcrystalline cellulose PH 112.

Load step 4 blend into the main bowl of planetary mixer and mix for 15 min.

Dry Mixing:

Then add remaining quantity of previously mixed Microcrystalline cellulose PH 112, Starch Plain, Cros carmellose sodium, Polyplasdone XL10 and Colloidal silicon dioxide and mix for 20 min.

Compression

Compress in a compression machine (using 7.5×4.5 mm—punch).

Packing

A container closure system was selected. Based on preformulation studies and a stability study, misoprostol (1% HPMC Dispersion) is hygroscopic in nature and also susceptible to degradation in presence of heat, light and humidity. Thus the tablet requires additional packaging precautions to protect the drug substance from heat, high humidity and light. Based on a sample Alu/Alu packing is suitable for this product.

Example 2: Disintegration Time

The disintegration time of tablets manufactured according to Example 1 were measured initially (right after manufacture) as well as after several months. The tablets were packed in Alu-Alu blister packs, maintained at 30±2° C. and 65±5% RH. The disintegration time was measured according to European Pharmacopoeia 8.0, using Disintegration apparatus A, placing one tablet in each of the 6 tubes of the basket without disc. The apparatus was operated using water medium as the immersion fluid, maintained at 37±0.5° C. After disintegration of the tablets the basket was lifted from the fluid, and all of the tablets had disintegrated completely.

The measured disintegration times are provided in the table below.

3^(rd) 6^(th) 9^(th) 12^(th) 18^(th) Initial month month month month month Disintegration 4 5 5 5 6 5 time seconds seconds seconds seconds seconds seconds

The tablets were found to have satisfactory disintegration time and stability.

Example 3: Comparison Experiment

In order to compare a tablet of the present invention with a tablet of the prior art, a tablet manufactured according to Example 1 (“Tablet A”) was subjected to the test of Example 4 of WO 2007/035954. Tablet A was compared to a commercially available Cytotec misoprostol tablet.

Three drops of water were placed on a glass plate. A tablet was placed on the drops of water. The plate was then tilted at a 90 degree angle. Tablet A of the present invention immediately began to swell and disintegrate upon contacting the water. When the plate was tilted, the disintegrated Tablet A slid without adhering to the glass plate. The Cytotec tablet showed far greater adherence to the glass plate.

Due to the short disintegration time, Tablet A will immediately form a dispersion upon contact with water or an aqueous medium. Therefore, Tablet A is not dependent on adherence to the vaginal tract upon administration.

Example 4: Comparison Experiment II—Disintegration

A tablet of the present invention was compared with a tablet of the prior art. A tablet manufactured according to Example 1 (“Tablet A”) was compared to a commercially available Cytotec misoprostol 0.2 mg tablet. Each tablet was placed in a beaker with a few drops of water. Photographs were recorded after 3, 7 and 15 seconds. Between each photograph, the beakers were very gently agitated by rotating the beakers.

FIG. 2A shows the tablets before being subjected to a disintegration experiment. Tablet A is on the left side, Cytotec is on the right side.

FIG. 2B shows the tablets 3 seconds after being placed in beakers with a few drops of water.

FIG. 2C shows the tablets 7 seconds after being placed in beakers with a few drops of water.

FIG. 2D shows the tablets 15 seconds after being placed in beakers with a few drops of water.

A dispersion is formed immediately after bringing Tablet A in contact with water. For Cytotec, no dispersion is formed, large flakes are formed, and the Cytotec tablet is not suitable for sublingual administration. Further, vaginal administration would require the Cytotec tablet to stay for a prolonged time in the vaginal tract.

Example 5: Comparison Experiment III— Dispersibility and Sieve Testing

Experiments were conducted to determine whether tablets of the invention and tablets of the prior art are dispersible tablets. Tablets manufactured according to Example 1 (“Tablet A”), comprising 25 μg misoprostol, were compared to commercially available Cytotec tablets, comprising misoprostol 0.2 mg.

Dispersibility test were performed using water at room temperature. Two tablets of Tablet A were mixed with 100 ml water (Mixture I), and two tablets of Cytotec were mixed with 100 ml (Mixture II) water in both cases while stirring for 180 seconds. For Tablet A, a dispersion forms within a few seconds. For Cytotec, no dispersion is formed, the tablets disintegrate slowly and a suspension is formed. Upon discontinuing stirring, the dispersion comprising Tablet A remains stable, while precipitate is clearly visible in the bottom of the suspension comprising Cytotec.

The mixtures were poured through sieve screens #20, #30, #40, #60, #80, and #100, having apertures of 900 μm, 600 μm, 400 μm, 250 μm, 200 μm, and 140 μm. For Mixture II it was necessary to continue stirring until just before pouring, in order ensure substantially all of the mixture was poured into the sieve. This was not the case for Mixture I which had formed a stable dispersion.

Mixture I, passed through the screens #20, #30, #40 without leaving any trace of precipitate, while a small amount of precipitate was visible in screen #60. At least 90% of the precipitate was apparent in screens #80 and #100 (FIG. 3A upper row, from left to right: sieve #20, #30, #40; lower row: sieve #60, #80, #100). Upon pouring Mixture II through the screens, particles remained in all sieve screens (FIG. 3B upper row, from left to right: sieve #20, #30, #40; lower row: sieve #60, #80, #100).

It was thus confirmed that Tablet A is a dispersible tablet, while Cytotec is not a dispersible tablet.

Additional experiments were conducted using larger amounts of water mixed with the Cytotec tablets, but no dispersions were formed, and particles remained in all the sieve screens.

Example 6: Compositions of the Invention

The table below provides manufactured (A) or contemplated (B and C) compositions of the invention.

Tablet C A B 200 μg tablet 25 μg tablet 200 μg tablet w/o Maize starch (mg/tablet) (mg/tablet) (mg/tablet) Misoprostol 2.5 20 20 (as 1% HPMC dispersion) Microcrystalline cellulose 69.5 57 62 Maize starch 10 5 0 Croscarmellose sodium 10 10 10 Crospovidone 10 10 10 Colloidal anhydrous silica 1 1 1 Total (mg) 103 103 103

Example 7: Clinical Studies

Cytotec tablets contain 200 micrograms (μg) of the active substance, misoprostol. The other ingredients are indicated to be: microcrystalline cellulose, sodium starch glycolate, hydrogenated castor oil, and hypromellose (E464). Cytotec tablets are white to off white hexagonal tablets scored on both sides. According to the package leaflet, the tablets may help prevent getting ulcers in the stomach or duodenum, and can also be used to heal existing ulcers. Patients are warned against using Cytotec if they are pregnant or trying to become pregnant, because it may cause a miscarriage according to the leaflet. According to the leaflet, patients should take two 200 microgram Cytotec tablets twice a day with food, or alternatively one Cytotec tablet four times a day, at regular intervals with food.

Cytotec tablets containing 200 micrograms (μg) misoprostol may be mixed with water to produce mixtures comprising solid residues. Solid tablets according to the invention (Tablet A) comprising 25 μg misoprostol were compared to 200 μg Cytotec tablets mixed with and diluted to 200 ml with water (CYTOTEC), of which either 25 or 50 ml was administered orally. The mixture CYTOTEC is presently used as off-label treatment in Sweden for labor induction. Note that the dosage of 200 μg of the Cytotec tablets make them unsuitable for providing dosages of 25 or 50 μg without division of the tablet. However, the tablets have a hexagonal shape with one groove making it difficult to divide the tablets precisely in ⅛ or ¼ fractions.

A trial was performed giving misoprostol for the induction of labor. The four (4) treatment groups comprise oral administration of 25 μg 2-hourly and 50 μg 4-hourly, comparing Tablet A and CYTOTEC for each administration dosage. Each group consisted of 12 women. The results are provided below. The symbol t_(1/2) denotes the terminal half-life.

50 μg 4-hourly Mean t_(1/2) (hrs) Tablet A 0.57 CYTOTEC 0.70 Vaginal delivery Tablet A 11 (of 12 women) CYTOTEC  5 (of 12 women) Duration (hrs) of Tablet A 20.5 Induction to delivery CYTOTEC 27.5 25 μg 2-hourly Mean t_(1/2) (hrs) Tablet A 0.43 CYTOTEC 0.60 Vaginal delivery Tablet A  9 (of 12 women) CYTOTEC 11 (of 12 women) Duration (hrs) of Tablet A 17.9 Induction to delivery CYTOTEC 25.5

These results indicate that the Mean t_(1/2) is shorter for Tablet A than for CYTOTEC. Further, the results indicate that the duration of induction to delivery is shorter for Tablet A than for CYTOTEC. For the 50 μg 4-hourly groups Tablet A provides a desirable higher number of vaginal deliveries (the remaining women being Caesarean or instrumental), than CYTOTEC. For the 25 μg 2-hourly groups, the difference of number of vaginal deliveries appears to be too small to make any conclusion of efficacy upon comparing Tablet A with CYTOTEC.

Without being bound by theory, it may be speculated as follows. Tablet A, which is free from extended release agents because it is designed to be suitable for sublingual administration, provides a shorter t_(1/2) compared to CYTOTEC. The active ingredient is immediately dispersed upon oral administration as a tablet, providing faster uptake of the active ingredient. CYTOTEC has longer t_(1/2) due to the presence of an extended release agent. Apparently, the extended release agent retards the uptake of the active ingredient, even if the Cytotec tablet is administered as a mixture with water. It is speculated that the active ingredient, misoprostol, is intimately mixed with the extended release agent of Cytotec, providing a longer release time, resulting in longer t_(1/2) and leading to longer duration of induction of delivery times. It is speculated that for Tablet A a more sudden increase (followed by decrease) of the concentration of misoprostol, kick-starts processes provoking the shorter duration of induction to delivery times. 

1. A pharmaceutical dosage form comprising misoprostol, or a pharmaceutically acceptable salt thereof, as the sole active ingredient; wherein the dosage form has a content of 0.5-50 μg misoprostol, or an equivalent amount of a pharmaceutically acceptable salt thereof; and wherein the dosage form further comprises: i) 5-20 wt % crospovidone, ii) 5-20 wt % of a cross-linked polymer of carboxymethyl cellulose or a crosslinked sodium carboxymethyl cellulose, iii) 5-20 wt % starch, iv) 30-85 wt % microcrystalline cellulose, and v) 0.1-2 wt % flow agent, subject to the proviso that the total of ingredients i) through v) does not exceed 100 wt %.
 2. The pharmaceutical dosage form according to claim 1, wherein the dosage form is suitable for use in a treatment comprising cervical ripening or the induction of labor upon administration to a subject.
 3. The pharmaceutical dosage form according to claim 1, wherein said dosage form is suitable for administration to a pregnant woman.
 4. The pharmaceutical dosage form according to claim 1, wherein the dosage form is suitable for sublingual or oral administration.
 5. The pharmaceutical dosage form according to claim 1, wherein said pharmaceutical dosage form comprises: i. crospovidone at about 10 wt %, ii. croscarmellose sodium at about 10 wt %, and iii. starch at about 10 wt %.
 6. The pharmaceutical dosage form according to claim 1, wherein said pharmaceutical dosage form comprises 70 wt % microcrystalline cellulose.
 7. The pharmaceutical dosage form according to claim 1, wherein said flow agent is 1 wt % colloidal silicon dioxide.
 8. The pharmaceutical dosage form according to claim 1, wherein said starch is maize starch.
 9. The pharmaceutical dosage form according to claim 1, wherein the dosage form is free of any extended release agents.
 10. The pharmaceutical dosage form according to claim 1, wherein the dosage form comprises a coating.
 11. The pharmaceutical dosage form according to claim 1, wherein the dosage form is an immediate release tablet.
 12. The pharmaceutical dosage form according to claim 1, wherein the dosage form has a disintegration time of less than 15 seconds as measured using Disintegration Apparatus A according to European Pharmacopoeia 8.0, wherein the apparatus comprises a basket without disc and the basket comprises 6 tubes, and wherein the apparatus is operated after placing one pharmaceutical dosage form in each of the 6 tubes and using an aqueous medium as the immersion fluid, maintained at 37±2° C.
 13. The pharmaceutical dosage form according to claim 12, wherein said dosage form has a disintegration time of less than 10 seconds.
 14. The pharmaceutical dosage form according to claim 1, wherein the dosage form disintegrates upon contact with 10 drops of water.
 15. The pharmaceutical dosage form according to claim 1, wherein the dosage form disintegrates upon contact with 3 drops of water.
 16. The pharmaceutical dosage form according to claim 1, wherein said dosage form allows dispersion in 100 ml water at 25° C. within 3 minutes upon stirring, thereby providing a dispersion, said dispersion passing through a sieve screen with a nominal mesh aperture of 710 μm, wherein the dosage form cannot pass through the sieve screen before dispersion in water.
 17. The pharmaceutical dosage form according to claim 1, wherein said dosage form allows dispersion in 100 ml water at 25° C. within 1 minute or preferably within 30 seconds, upon stirring, thereby providing a dispersion, said dispersion passing through a sieve screen with a nominal mesh aperture of 710 μm, wherein the dosage form cannot pass through the sieve screen before dispersion in water.
 18. The pharmaceutical dosage form according to claim 1, wherein the dosage form, upon being placed on three drops of water on a glass plate which is subsequently tilted at a 90 degrees angle, slides.
 19. The pharmaceutical dosage form according to claim 18, wherein the dosage form, upon being placed on three drops of water on a glass plate which is subsequently tilted at a 90 degrees angle, slides without adhering to the glass plate.
 20. A pharmaceutical dosage form comprising misoprostol, or a pharmaceutically acceptable salt thereof, as the sole active ingredient; wherein the dosage form has a content of 0.5-50 μg misoprostol, or an equivalent amount of a pharmaceutically acceptable salt thereof; and wherein the dosage form further comprises: i) 8-12 wt % crospovidone, ii) 8-12 wt % of a cross-linked polymer of carboxymethyl cellulose or a crosslinked sodium carboxymethyl cellulose, iii) 5-12 wt % starch, iv) 60-75 wt % microcrystalline cellulose, and v) 0.1-2 wt % flow agent, subject to the proviso that the total of ingredients i) through v) does not exceed 100 wt %. 